This proposal continues a study of the mechanism of action of antidepressant treatments with a focus on the regulation of 5HT- 2 receptors. During the previous award period, studies of antidepressant-induced alterations in 5HT-2 receptors shifted from radioligand binding analyses of the 5H-T-2 recognition site to studies of the transmembrane signaling pathway, hydrolysis of inositol lipids. These studies have discovered a new site of action of antidepressant drugs at a point distal to the cell surface recognition site. In future studies, a cell culture model of 5HT-2 receptors will be developed in order to examine the mechanism of desensitization and down regulation of 5HT-2 receptor induced by mianserin and other atypical antidepressants which have a high affinity for the 5HT-2 site. The proposed experiments are designed to examine 5HT - 2 receptor signal transduction all along the signal cascade; from the cell surface recognition site ketanserin binding), to the transmembrane signaling pathway (phosphoinositide hydrolysis), to the formation of intracellular second messengers (IP3 and diacyglycerol), to intracellular responses mediated by the 5HT-2/phospholipase C pathway (mobilization of internal calcium stores). These studies will serve as a supplement and guide to continued in vivo studies of delayed, adaptive changes in the 5HT-2 receptor system after chronic antidepressant treatments. The in vivo studies will test the hypothesis that desensitization of the 5HT-2 receptor linked to phosphoinositide hydrolysis is a common action of the various classes of antidepressant treatments. Studies to date have demonstrated a desensitization of the 5HT-2 receptor after the tricyclic antidepressant amitriptyline, after the atypical antidepressant mianserin, and after sertraline, which is representative of a new class of antidepressants. Additional treatment classes to be evaluated are electroconvulsive shocks, MAO inhibitors, and the combination of lithium with tricyclic antidepressants and selective 5HT uptake inhibitors. The mechanism of desensitization of the 5HT-2 receptor after chronic antidepressant treatment will be explored by measuring the number and affinity of cell surface recognition sites in radioligand binding studies, the catalytic activity of phospholipase C and the coupling efficiency of the 5HT-2 recognition site and phospholipase C estimated by changes in agonists affinity states and in the GTP- induced shift in agonist affinity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
2R01MH026463-10
Application #
3374966
Study Section
Neurosciences Research Review Committee (BPN)
Project Start
1975-06-15
Project End
1990-11-30
Budget Start
1987-12-01
Budget End
1988-11-30
Support Year
10
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37203
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Gillespie, D D; Manier, D H; Sanders-Bush, E et al. (1988) The serotonin/norepinephrine-link in brain. II. Role of serotonin in the regulation of beta adrenoceptors in the low agonist affinity conformation. J Pharmacol Exp Ther 244:154-9
Sulser, F; Sanders-Bush, E (1987) The serotonin-norepinephrine link hypothesis of affective disorders: receptor-receptor interactions in brain. Adv Exp Med Biol 221:489-502
Manier, D H; Gillespie, D D; Sanders-Bush, E et al. (1987) The serotonin/noradrenaline-link in brain. I. The role of noradrenaline and serotonin in the regulation of density and function of beta adrenoceptors and its alteration by desipramine. Naunyn Schmiedebergs Arch Pharmacol 335:109-14
Sanders-Bush, E; Breeding, M; Roznoski, M (1987) 5HT2 binding sites after mianserin: comparison of loss of sites and brain levels of drug. Eur J Pharmacol 133:199-204
Conn, P J; Sanders-Bush, E (1987) Central serotonin receptors: effector systems, physiological roles and regulation. Psychopharmacology (Berl) 92:267-77
Conn, P J; Sanders-Bush, E (1986) Regulation of serotonin-stimulated phosphoinositide hydrolysis: relation to the serotonin 5-HT-2 binding site. J Neurosci 6:3669-75
Blackshear, M A; Martin, L L; Sanders-Bush, E (1986) Adaptive changes in the 5-HT2 binding site after chronic administration of agonists and antagonists. Neuropharmacology 25:1267-71